The transient receptor potential channel TRPM7 is a member of the TRP superfamily of cation channels that comprises greater than 20 cation channels that play critical roles in varied processes within the body. TRP channels are integral membrane proteins in which the ion-conducting pores are formed by six membrane-spanning helical segments that are similar to those of voltage-gated potassium channels and cyclic nucleotide-gated channels. TRP channels are divided into three families based on their homology. The families are the short TRP channel family, the osm TRP family, and the long TRP family. Long TRP channels can be distinguished by their having particularly long extensions outside the channel segment. Long TRP channels are involved in critical control mechanisms regulating cell growth, differentiation and death ((Montell et al., 2002, Harteneck et al., 2000).
The TRPM7 channel belongs to the long TRP family. The human TRPM7 protein was first identified by Runnels et al (2001)) and was identified as a bifunctional protein with kinase and ion channel activities. In another study by Nadler et al. (2001), TRPM7 was identified as a Mg-ATP regulated cation channel required for cell viability. Runnels et al. (2002) reported that TRPM7 is a calcium-permeant ion channel. It was also reported that the kinase domain of TRPM7 directly associates with the C2 domain of phospholipase C (PLC) and that 4,5-biphophate (PIP2), the substrate of PLC, is a key regulator of TRPM7. The TRPM7 channel produces pronounced outward currents at nonphysiological voltages ranging from +50 to +100 mV and small inward currents at negative potentials between −100 to −40 mV when expressed heterologously in mammalian cells (Jiang et al., 2005) The basal activity of TRPM7 was originally reported to be regulated by millimolar levels of intracellular mgATP and Mg2+. It is now recognized that the TRPM7 channel is unlikely to be gated by ATP (it was the Mg2+ in the MgATP that, when depleted, caused the channel to open). TRPM7 is activated by depletion of intracellular Mg2+, and is inhibited by high concentrations of Mg2+ with an IC50 of about 0.6 mM (Nadler et al., supra, Jiang et al., supra). The TRPM7 channel is also known as the CHAK, CHAK1, LTRPC7, FLJ20117 or TRP-PLIK channel. The TRPM7 channel is also activated by a reduction in extraellular divalent cation levels, especially Mg2+ and Va2+. More recently, the TRPM7 channel has been shown to be involved in ischemic CNS injury and anoxic neuronal cell death (Aarts et al., 2003; Aarts and Tymianski, 2005a, Aarts and Tymianski, 2005b).
Excitotoxicity in brain ischemia triggers neuronal death and neurological disability, and yet these are not prevented by antiexcitotoxic therapy (AET) in humans. Aarts et al. (2003) have shown that in murine neurons subjected to prolonged oxygen glucose deprivation (OGD), AET unmasks a dominant death mechanism perpetuated by a Ca2+-permeable nonselective cation conductance (IOGD). IOGD was activated by reactive oxygen/nitrogen species (ROS), and permitted neuronal Ca2+ overload and further ROS production despite AET. IOGD currents corresponded to those evoked in HEK-293 cells expressing the nonselective cation conductance TRPM7. In cortical neurons, blocking IOGD or suppressing TRPM7 expression blocked TRPM7 currents, anoxic 45Ca2+ uptake, ROS production, and anoxic death. TRPM7 suppression eliminated the need for AET to rescue anoxic neurons and permitted the survival of neurons previously destined to die from prolonged anoxia. Thus, excitotoxicity may be is a subset of a greater overall anoxic cell death mechanism, in which TRPM7 channels play a key role.
Exposure to low Ca(2+) and/or Mg(2+) is tolerated by cardiac myocytes, astrocytes, and neurons, but restoration to normal divalent cation levels paradoxically causes Ca(2+) overload and cell death. This phenomenon has been called the “Ca(2+) paradox” of ischemia-reperfusion. The mechanism by which a decrease in extracellular Ca(2+) and Mg(2+) is “detected” and triggers subsequent cell death is unknown. Transient periods of brain ischemia are characterized by substantial decreases in extracellular Ca(2+) and Mg(2+) that mimic the initial condition of the Ca(2+) paradox. Wei et al. (2007) have shown that In CA1 hippocampal neurons, lowering extracellular divalents stimulates a nonselective cation current. They showed that this current resembles TRPM7 currents in several ways. Both (i) respond to transient decreases in extracellular divalents with inward currents and cell excitation, (ii) demonstrate outward rectification that depends on the presence of extracellular divalents, (iii) are inhibited by physiological concentrations of intracellular Mg(2+), (iv) are enhanced by intracellular phosphatidylinositol 4,5-bisphosphate (PIP(2)), and (v) can be inhibited by Galphaq-linked G protein-coupled receptors linked to phospholipase C beta1-induced hydrolysis of PIP(2). Furthermore, suppression of TRPM7 expression in hippocampal neurons strongly depressed the inward currents evoked by lowering extracellular divalents. Finally, they show that activation of TRPM7 channels by lowering divalents significantly contributes to cell death. Together, the results suggest that TRPM7 contributes to the mechanism by which hippocampal neurons “detect” reductions in extracellular divalents and provide a means by which TRPM7 contributes to neuronal death during transient brain ischemia.